DESCRIPTION: While long term combined antiretroviral therapy (cART) has greatly improved survival rates among AIDS patients, a substantial proportion of HIV-1 infected individuals continue to develop comorbidities including heart failure (HF) secondary to left ventricular dysfunction at higher rates than non-HIV-1 individuals. The underlying mechanisms whereby HIV-1 increases susceptibility to HF remain poorly understood. In this respect, HIV-1 Tat, which is produced and released by the latent viral reservoir and upon its circulation can be taken up by uninfected cells, has received special attention due to its ability to induce an array of dysregulatory events that perturb cell and organ function. HIV-1 Tat has the capacity to induce injury and promote death in a broad range of cells including myocytes, and its expression promotes cardiac disease in laboratory animals. Our recent studies demonstrate that HIV-1 Tat physically associates with BAG3, a stress induced protein which is involved in protein quality control, and modulates autophagy and apoptosis. BAG3 is critical for normal cardiac development and maintenance as BAG3 knockout mice develop left ventricular (LV) dysfunction and have a shortened lifespan. Furthermore, recent studies have identified a potential role for BAG3 in patients with HF as heterozygous mutations that decrease the level of BAG3 have been identified in patients with HF within families who develop a heritable form of dilated cardiomyopathy. Moreover, ventricular myocardium isolated from failing human hearts examined at the time of heart transplantation exhibit nearly 50% reduction in BAG3 levels in cardiac tissue, all of which supports the importance of BAG3 for healthy heart function. At the subcellular level, the association of BAG3 with the actin capping protein, CapZ?1, promotes its complexation with Hsp70, events that stabilize CapZ?1and facilitate its proper subcellular distribution in cardiomyocytes. In addition, BAG3 is an important regulator of filamin and myopodin and regulates protein turnover by autophagy in cardiomyocytes. Our preliminary results suggest that the interplay between BAG3 and HIV-1 Tat impacts the ability of BAG3 to regulate several pathways involved in the structural and functional integrity of cardiomyocytes. Thus, one can envision a model in which the inactivation of BAG3, upon its association with HIV-1 Tat, recapitulates the clinical manifestations seen in patients with heart failure associated with low/dysfunctional BAG3. By capitalizing on the expertise of two groups of accomplished investigators in cardiovascular research and in HIV-1 pathogenesis and BAG3 biology, we will investigate the cellular and molecular mechanisms involved in HIV-1 induced cardiomyopathy in cell cultures, animal models, and clinical samples. The outcome of these studies will provide a unique set of information aimed at developing prognostic biomarkers of disease severity and therapeutic strategies for treating HIV-1 associated cardiomyopathy.